The present application is related to Merck 19275, 18996 and 18996IA.
The present invention is concerned with a novel process for synthesizing compounds that inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as derivatives of Compound J in the Examples below. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et at., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et at., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. Compounds, including certain oligopeptide analogs that can be made from the novel processes of this invention are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993. See, for example, Compound J therein.
Previously, the synthesis of Compound J and related compounds was accomplished via a 12-step procedure. This procedure is described in EPO 541,168. The extreme length of this route (12 steps), renders this process time consuming and labor intensive, and it requires the use of many presently expensive reagents and a presently expensive starting material. A route requiring fewer reaction steps and reagents would provide desirable economical and time-saving benefits.
Applicants have identified and synthesized a variety of derivatives of Compound J, by incubating Compound J with a selected microbial system, MA7074. The new compounds are active and potent inhibitors of HIV protease.
The 2,3-cis-hydroxy analogue of Compound J has previously been synthesized by chemical synthesis. Chemical reactions are usually complex, expensive, and due to the usage of various chemicals and solvents are environmentally damaging. The 3-Keto analogue of Compound J is a novel structure and showed less HIV-protease activity than Compound J. Because of the availability of a keto group this compound is useful as starting material for the synthesis of other derivatives.